Design of Proteins with Specified Thermal Properties

Abstract

We propose a new and effective means for designing stable and fast-folding polypeptide sequences using a cumulant expansion of the molecular partition function. This method is unique in that $T_Z$, the ``cumulant design temperature'' entered as a parameter in the design process, is predicted also to be the optimal folding temperature. The method was tested using monte-carlo folding simulations of the designed sequences, at various folding temperatures $T_F$. (Folding simulations were run on a cubic lattice for computational convenience, but the design process itself is lattice-independent.) Simulations confirmed that, over a wide range of $T_Z$, all designed sequences folded rapidly when $T_F\approx T_Z$. Additionally, highly thermostable model proteins were created simply by designing with high $T_Z$. The mechanism proposed in these studies provides a plausible pathway for the evolutionary design of biologically active proteins, which {\em must} fold and remain stable within a relatively narrow range of temperatures.

12 pages (RevTeX) + 4 postscript figures